Therapeutic agent for chronic obstructive pulmonary disease

ABSTRACT

Disclosed is a method for the prevention and/or treatment of a chronic obstructive pulmonary disease by administrating a 5-membered cyclic compound represented by the formula below: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or salt: wherein X represents an oxygen or sulfur atom; R 1  represents a hydrogen atom, a substituted or unsubstituted alkyl or the like; R 2  represents a hydrogen atom, a substituted or unsubstituted alkyl or the like; Y 1  represents single bond, a substituted or unsubstituted alkylene or the like; the wavy line means an (E) or (Z) coordination; R 3  represents a hydrogen atom, a substituted or unsubstituted aryl or the like; Y 2  represents a substituted or unsubstituted alkylene or an alkenylene; R 4  represents a hydrogen atom, a substituted or unsubstituted alkanoyl or the like; and R 5  represents a hydrogen atom or a substituted or unsubstituted alkyl.

This application is a continuation application claiming priority under35 U.S.C. §120 of U.S. application Ser. No. 11/919,135 filed on Oct. 24,2007. U.S. application Ser. No. 11/919,135 is the national phase under35 U.S.C. §371 of PCT International Application No. PCT/JP2006/309028filed on Apr. 28, 2006, which claims priority under 35 U.S.C. §119 ofJapanese Application No. 2005-132871 filed on Apr. 28, 2005 and JapaneseApplication No. 2005-154008 filed on May 26, 2005.

TECHNICAL FIELD

The present invention relates to a pharmaceutical use of a 5-memberedring compound described in WO 02/02542, or a salt or a pharmaceuticalcomposition thereof. More particularly, the present invention relates toa pharmaceutical use of a 5-membered ring compound, or a salt or apharmaceutical composition thereof, which is effective for preventionand/or treatment of a chronic obstructive pulmonary disease (COPD).

BACKGROUND ART

It has been reported in Patent Document 1 that a 5-membered ringcompound inhibits a late asthmatic response, but no disclosure has beenfound about an agent for preventing and/or treating COPD which aredifferent from asthma in mechanism of activity and utility.

A chronic obstructive pulmonary disease had been defined as a diseasecharacterized by airflow obstruction (obstructive ventilatoryimpairment) caused by chronic bronchitis, lung emphysema or acomplication thereof, but has been defined as “a disease statecharacterized by airflow limitation that is not fully reversible. Theairflow limitation is usually both progressive and associated with anabnormal inflammatory response of the lungs to noxious particles orgases” in the international guideline GOLD (Global initiative forChronic Obstructive Lung Disease) published in April, 2001. COPD is alsoreferred to as “a chronic nonspecific lung disease which is manifestedan obstructive ventilatory impairment due to lung emphysema or smallairway disease caused by harmful gas or particles of cigarette.”Cigarette smoking history is important in terms of clinical history.Cigarette smoking is a clear cause of COPD, and an obstructiveventilatory impairment progresses to a chronic progressive disease dueto cigarette smoking. Any other causes of COPD include air pollution andoccupation (occupation which breathes the fumes, for example a chef),and a promoting factor includes infection. COPD is a progressiveirreversible chronic disease, and most part of causes thereof iscigarette smoking. Accordingly, treatment which delays a progression ofthe disease is smoking cessation, and treatment which significantlycontributes to a prognostic improvement after respiratory failure (PaO₂60 mmHg and below) is a domiciliary oxygen therapy.

It has been reported that neutrophil numbers and concentrations of TNF-αand IL-8 rise by analysis of bronchoalveolar fluid in COPD patients(Non-patent Document 1). Also, it has been suggested by analysis of COPDpatients or animal model of disease that an anti TNF-α therapy can beeffective for treatment of COPD and inhibition of progression(Non-patent Document 2). Accordingly, an agent effective for treatingand/or preventing COPD may be such drugs that inhibit depressedproduction of IL-8, infiltration/activation of neutrophil, depressedproduction of TNF-α, infiltration/activation of alveolar macrophagewhich is one of inflammatory cells which produce IL-8 or TNF-α,thickening of airway epithelium or alveolar wall, or a responsiblefactor thereof, and further, emphysematous lesion including destructionof alveolar wall or a responsible factor thereof.

-   Patent Document 1: WO 02/02542-   Non-patent Document 1: Am. J. Respir. Crit. Care Med. 153, 530-534    (1996)-   Non-patent Document 2: New Drugs for Asthma, Allergy and COPD.,    Prog. Respir, Res., Basel, Karger, 31; 247-250 (2001)

DISCLOSURE OF INVENTION Problems to be Resolved by the Invention

The present invention is directed to provide a therapeutic agent usefulfor improving a chronic obstructive pulmonary disease, comprising a5-membered ring compound as an active ingredient. Specifically, thepresent invention is directed to provide a therapeutic agent useful forimproving a chronic obstructive pulmonary disease, comprising as anactive ingredientN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholinophenyl)-thiazol-3(2H)-yl]ethyl}-N′-methylurea.Additionally, the present invention is, in particular, directed toprovide a therapeutic agent useful for improving a chronic obstructivepulmonary disease, comprising as an active ingredientN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholinophenyl)-thiazol-3(2H)-yl]ethyl}-N′-methylurea,which have been found to have a high therapeutic effect and a highsafety without problem of monometabolism.

Means of Solving the Problems

The present inventors have studied to solve the above problems, andfound that the present compound inhibits infiltration of an alveolarmacrophage, which is one of inflammatory cells which produce TNF-α, andthat the problems can be solved according to the following procedures.

More specifically, the present invention is as follows:

(1) A method for preventing and/or treating a chronic obstructivepulmonary disease by administering a 5-membered ring compound of theformula (1):

wherein X is oxygen atom or sulfur atom;

R¹ is hydrogen atom, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, or substituted or unsubstituted monocyclic orbicyclic heterocycle;

R² is hydrogen atom, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted monocyclic or bicyclicheterocycle, or —CON(R⁶)R⁷;

R⁶ is hydrogen atom or substituted or unsubstituted alkyl; R⁷ issubstituted or unsubstituted aryl, substituted or unsubstitutedmonocyclic heterocycle, or substituted or unsubstituted alkyl; or

—N(R⁶)R⁷ may be cyclic imino;

Y¹ is single bond, substituted or unsubstituted alkylene,

—CO(CH₂)_(n)—, —SO₂(CH₂)_(n)—, —CONH(CH₂)_(n)—, —CSNH(CH₂)_(n)—, or—COO(CH₂)_(n)—;

n is integer of 0 to 5;

wavy line is (E)- or (Z)-coordination;

R³ is hydrogen atom, substituted or unsubstituted aryl, substituted orunsubstituted monocycle heterocycle, substituted or unsubstitutedbicyclic heterocycle, or substituted or unsubstituted cycloalkyl;

Y² is substituted or unsubstituted alkylene, or alkenylene;

R⁴ is hydrogen atom, substituted or unsubstituted alkanoyl, substitutedor unsubstituted alkyl, —COOR⁸, —SO₂R⁹, —COR¹⁰, —CON(R¹¹)R¹²,—CSN(R¹³)R¹¹, cycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted monocyclic heterocycle, —C(═NH)N(R¹⁵)R¹⁶; R⁵ ishydrogen atom, or substituted or unsubstituted alkyl; or —N(R⁴)R⁵ may becyclic imino;

R⁸ is substituted or unsubstituted alkyl, cycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted monocyclicheterocycle; R⁹ is substituted or unsubstituted alkyl, substituted orunsubstituted aryl, or substituted or unsubstituted monocyclicheterocycle; R¹⁰ is cycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted monocyclic heterocycle; R¹¹ is hydrogenatom or alkyl; R¹² is hydrogen atom, substituted or unsubstituted alkyl,cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylcarbonyl, or substituted or unsubstituted monocycleheterocycle; or —N(R¹¹)R¹² may be cyclic imino; R¹³ is hydrogen atom oralkyl; R¹⁴ is hydrogen atom, substituted or unsubstituted alkyl,cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylcarbonyl, or substituted or unsubstituted monocycleheterocycle; or —N(R¹³)R¹⁴ may be cyclic imino;

R¹⁵ is hydrogen atom or alkyl; R¹⁶ is hydrogen atom or substituted orunsubstituted alkyl; or —N(R¹⁵)R¹⁶ may be cyclic imino; or apharmaceutically acceptable salt or a prodrug thereof.

(2) The method for preventing and/or treating a chronic obstructivepulmonary disease of (1) wherein R¹ is hydrogen atom, X is sulfur atom,Y¹ is single bond, R² is substituted phenyl, —Y²—N(R⁴)(R⁵) is—CH₂CH₂—NH(CO)NHCH₃, R³ is meta-substituted phenyl.(3) The method for preventing and/or treating a chronic obstructivepulmonary disease of (1) wherein the 5-membered ring compound isN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureaof the formula (2):

(4) The method for prevention and/or treatment of (3) whereinN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureahas a crystal form of needles.(5) The method for prevention and/or treatment of (3) whereinN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureahas a melting point of 190-191° C.(6) An agent for preventing and/or treating a chronic obstructivepulmonary disease comprising a 5-membered ring compound of the formula(1):

wherein X is oxygen atom or sulfur atom;

R¹ is hydrogen atom, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, or substituted or unsubstituted monocyclic orbicyclic heterocycle;

R² is hydrogen atom, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted monocyclic or bicyclicheterocycle, or —CON(R⁶)R⁷;

R⁶ is hydrogen atom or substituted or unsubstituted alkyl; R⁷ issubstituted or unsubstituted aryl, substituted or unsubstitutedmonocyclic heterocycle, or substituted or unsubstituted alkyl; or—N(R⁶)R⁷ may be cyclic imino;

Y¹ is single bond, substituted or unsubstituted alkylene, —CO(CH₂)_(n)—,—SO₂(CH₂)_(n)—, —CONH(CH₂)_(n)—, —CSNH(CH₂)_(n)—, or —COO(CH₂)_(n)—;

n is integer of 0 to 5;

wavy line is (E)- or (Z)-coordination;

R³ is hydrogen atom, substituted or unsubstituted aryl, substituted orunsubstituted monocyclic heterocycle, substituted or unsubstitutedbicyclic heterocycle, or substituted or unsubstituted cycloalkyl;

Y² is substituted or unsubstituted alkylene, or alkenylene;

R⁴ is hydrogen atom, substituted or unsubstituted alkanoyl, substitutedor unsubstituted alkyl, —COOR⁸, —SO₂R⁹, —COR¹⁰, —CON(R¹¹)R¹²,—CSN(R¹³)R¹¹, cycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted monocyclic heterocycle, —C(═NH)N(R¹⁵)R¹⁶; R⁵ ishydrogen atom, or substituted or unsubstituted alkyl; or —N(R⁴)R⁵ may becyclic imino;

R⁸ is substituted or unsubstituted alkyl, cycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted monocyclicheterocycle; R⁹ is substituted or unsubstituted alkyl, substituted orunsubstituted aryl, or substituted or unsubstituted monocyclicheterocycle; R¹⁰ is cycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted monocyclic heterocycle; R¹¹ is hydrogenatom or alkyl; R¹² is hydrogen atom, substituted or unsubstituted alkyl,cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylcarbonyl, or substituted or unsubstituted monocyclicheterocycle; or —N(R¹¹)R¹² may be cyclic imino; R¹³ is hydrogen atom oralkyl; R¹⁴ is hydrogen atom, substituted or unsubstituted alkyl,cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylcarbonyl, or substituted or unsubstituted monocyclicheterocycle; or —N(R¹³)R¹⁴ may be cyclic imino;

R¹⁵ is hydrogen atom or alkyl; R¹⁶ is hydrogen atom or substituted orunsubstituted alkyl; or —N(R¹⁵)R¹⁶ may be cyclic imino; or apharmaceutically acceptable salt or a prodrug thereof.

(7) The agent for preventing and/or treating a chronic obstructivepulmonary disease of (6) wherein R¹ is hydrogen atom, X is sulfur atom,Y¹ is single bond, R² is substituted phenyl, —Y²—N(R⁴)R⁵ is—CH₂CH₂—NH(CO)NHCH₃, R³ is meta-substituted phenyl.(8) The agent for preventing and/or treating a chronic obstructivepulmonary disease of (6) wherein the 5-membered ring compound isN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylurea.(9) The agent for preventing and/or treating a chronic obstructivepulmonary disease of (8) whereinN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureahas a crystal form of needles.(10) The agent for preventing and/or treating a chronic obstructivepulmonary disease of (8) whereinN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureahas a melting point of 190-191° C.(11) A method for preventing and/or treating a chronic obstructivepulmonary disease by administering a 5-membered ring compound of theformula (1):

wherein X is oxygen atom or sulfur atom;

R¹ is hydrogen atom, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, or substituted or unsubstituted monocyclic orbicyclic heterocycle;

R² is hydrogen atom, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted monocyclic or bicyclicheterocycle, or —CON(R⁶)R⁷;

R⁶ is hydrogen atom or substituted or unsubstituted alkyl; R⁷ issubstituted or unsubstituted aryl, substituted or unsubstitutedmonocyclic heterocycle, or substituted or unsubstituted alkyl; or—N(R⁶)R⁷ may be cyclic imino;

Y¹ is single bond, substituted or unsubstituted alkylene, —CO(CH₂)_(n)—,—SO₂(CH₂)_(n)—, —CONH(CH₂)_(n)—, —CSNH(CH₂)_(n)—, or —COO(CH₂)_(n)—;

n is integer of 0 to 5;

wavy line is (E)- or (Z)-coordination;

R³ is hydrogen atom, substituted or unsubstituted aryl, substituted orunsubstituted monocyclic heterocycle, substituted or unsubstitutedbicyclic heterocycle, or substituted or unsubstituted cycloalkyl;

Y² is substituted or unsubstituted alkylene, or alkenylene;

R⁴ is hydrogen atom, substituted or unsubstituted alkanoyl, substitutedor unsubstituted alkyl, —COOR⁸, —SO₂R⁹, —COR¹⁰,

—CON(R¹¹)R¹², —CSN(R¹³)R¹⁴, cycloalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted monocyclic heterocycle,—C(═NH)N(R¹⁵)R¹⁶; R⁵ is hydrogen atom, or substituted or unsubstitutedalkyl; or —N(R⁴)R⁵ may be cyclic imino;

R⁸ is substituted or unsubstituted alkyl, cycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted monocyclicheterocycle; R⁹ is substituted or unsubstituted alkyl, substituted orunsubstituted aryl, or substituted or unsubstituted monocyclicheterocycle; R¹⁰ is cycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted monocyclic heterocycle; R¹¹ is hydrogenatom or alkyl; R¹² is hydrogen atom, substituted or unsubstituted alkyl,cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylcarbonyl, or substituted or unsubstituted monocyclicheterocycle; or —N(R¹¹)R¹² may be cyclic imino; R¹³ is hydrogen atom oralkyl; R¹⁴ is hydrogen atom, substituted or unsubstituted alkyl,cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylcarbonyl, or substituted or unsubstituted monocyclicheterocycle; or —N(R¹³)R¹⁴ may be cyclic imino;

R¹⁵ is hydrogen atom or alkyl; R¹⁶ is hydrogen atom or substituted orunsubstituted alkyl; or —N(R¹⁵)R¹⁶ may be cyclic imino or apharmaceutically acceptable salt or a prodrug thereof in combinationwith a steroid or an anticholinergic agent as a companion drug.

(12) The method for preventing and/or treating a chronic obstructivepulmonary disease of (11) wherein R¹ is hydrogen atom, X is sulfur atom,Y¹ is single bond, R² is substituted phenyl, —Y²N(R⁴)R⁵ is—CH₂CH₂—NH(CO)NHCH₃, R³ is meta-substituted phenyl.(13) The method for preventing and/or treating a chronic obstructivepulmonary disease of (11) wherein the 5-membered ring compound isN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureaand the companion drug is a steroid.(14) The method for preventing and/or treating a chronic obstructivepulmonary disease of (11) wherein the 5-membered ring compound isN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureaand the companion drug is an anticholinergic agent.(15) An agent for preventing and/or treating a chronic obstructivepulmonary disease comprising a 5-membered ring compound of the formula(1):

wherein X is oxygen atom or sulfur atom;

R¹ is hydrogen atom, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, or substituted or unsubstituted monocyclic orbicyclic heterocycle;

R² is hydrogen atom, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted monocyclic or bicyclicheterocycle, or —CON(R⁶)R⁷;

R⁶ is hydrogen atom or substituted or unsubstituted alkyl; R⁷ issubstituted or unsubstituted aryl, substituted or unsubstitutedmonocyclic heterocycle, or substituted or unsubstituted alkyl; or—N(R⁶)R⁷ may be cyclic imino;

Y¹ is single bond, substituted or unsubstituted alkylene, —CO(CH₂)_(n)—,—SO₂(CH₂)_(n)—, —CONH(CH₂)_(n)—, —CSNH(CH₂)_(n)—, or —COO(CH₂)_(n)—;

n is integer of 0 to 5;

wavy line is (E)- or (Z)-coordination;

R³ is hydrogen atom, substituted or unsubstituted aryl, substituted orunsubstituted monocyclic heterocycle, substituted or unsubstitutedbicyclic heterocycle, or substituted or unsubstituted cycloalkyl;

Y² is substituted or unsubstituted alkylene, or alkenylene;

R⁴ is hydrogen atom, substituted or unsubstituted alkanoyl, substitutedor unsubstituted alkyl, —COOR⁸, —SO₂R⁹, —COR¹⁰, —CON(R¹¹)R¹²,—CSN(R¹³)R¹¹, cycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted monocyclic heterocycle, —C(═NH)N(R¹⁵)R¹⁶; R⁵ ishydrogen atom, or substituted or unsubstituted alkyl; or —N(R⁴)R⁵ may becyclic imino;

R⁸ is substituted or unsubstituted alkyl, cycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted monocyclicheterocycle; R⁹ is substituted or unsubstituted alkyl, substituted orunsubstituted aryl, or substituted or unsubstituted monocyclicheterocycle; R¹⁰ is cycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted monocyclic heterocycle; R¹¹ is hydrogenatom or alkyl; R¹² is hydrogen atom, substituted or unsubstituted alkyl,cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylcarbonyl, or substituted or unsubstituted monocyclicheterocycle; or —N(R¹¹)R¹² may be cyclic imino; R¹³ is hydrogen atom oralkyl; R¹⁴ is hydrogen atom, substituted or unsubstituted alkyl,cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylcarbonyl, or substituted or unsubstituted monocyclicheterocycle; or —N(R¹³)R¹⁴ may be cyclic imino;

R¹⁵ is hydrogen atom or alkyl; R¹⁶ is hydrogen atom or substituted orunsubstituted alkyl; or —N(R¹⁵)R¹⁶ may be cyclic imino; or apharmaceutically acceptable salt or a prodrug thereof in combinationwith a steroid or an anticholinergic agent as a companion drug.

(16) The agent for preventing and/or treating a chronic obstructivepulmonary disease of (15) wherein R¹ is hydrogen atom, X is sulfur atom,Y¹ is single bond, R² is substituted phenyl, —Y²—N(R⁴)R⁵ is—CH₂CH₂—NH(CO)NHCH₃, R³ is meta-substituted phenyl.(17) The agent for preventing and/or treating a chronic obstructivepulmonary disease of (15) wherein the 5-membered ring compound isN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureaand the companion drug is a steroid.(18) The agent for preventing and/or treating a chronic obstructivepulmonary disease of (15) wherein the 5-membered ring compound isN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureaand the companion drug is an anticholinergic agent.(19)N-2-[2-[(3-Fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl)-N′-methylureaof the formula (2):

(20) The compound of (19) which has a crystal form of needles.(21) The compound of (19) which has a melting point of 190-191° C.

Effect of the Invention

According to the present invention, a chronic obstructive pulmonarydisease can be cured.

BEST MODE FOR CARRYING OUT THE INVENTION

Throughout the present specification, each substituent has the followingmeaning.

The term “alkyl” includes, for example, straight chain or branched chainC₁-C₆ alkyl, in particular methyl, ethyl, n-propyl, 2-propyl, n-butyl,2-butyl, 3-methyl-2-propyl, 1,1-dimethylethyl, n-pentyl, n-hexyl or thelike.

A substituent of the “substituted alkyl” includes, for example, hydroxy,halogen atom, amino, mono- or di-(alkyl)amino, carboxy, alkoxycarbonyl,alkoxy, carbamoyl, mono- or di-(alkyl)carbamoyl, cyclic imino,alkoxyalkoxy, hydroxyalkoxy, carboxyalkoxy, alkanoyloxy, aryloxy, aryl,arylcarbonylamino, arylamino, arylalkylamino, alkanoylamino, alkylthio,cycloalkyl, arylalkoxy, arylalkyl(alkyl)amino, arylsulfonyl,alkylsulfonyl, carbamoylalkoxy, mono- or di-(alkyl)carbamoyl-alkoxy,arylsulfonylamino, arylcarbamoylamino, or the like, wherein the alkyl isoptionally substituted by alkoxy, alkoxycarbonyl, carboxy, dialkylaminoor hydroxy, and the aryl is optionally substituted by alkyl, alkoxy,halogen atom or hydroxy. The substituent may be selected from the abovein single or two or more of the same or different ones. For example, thealkyl may be substituted by 1 to 3, preferably 1 to 2, of the same ordifferent substituent(s) as mentioned above. More preferable substituentof the “substituted alkyl” in R⁴ includes hydroxy, alkoxy, mono- ordi-(alkyl)amino, morpholino, carboxy, alkoxyalkoxy, hydroxyalkoxy,carboxyalkoxy or the like.

The term “alkyl substituted by halogen atom or hydroxy” includes, forexample, straight chain or branched chain C₁-C₆ alkyl substituted by 1to 3 of halogen atom(s) such as fluorine, chlorine, bromine, iodine orhydroxy, in particular fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, bromomethyl, fluoroethyl, 2,2,2-trifluoroethyl,3-fluoro-1-propyl, 3-fluoro-2-propyl, 4-fluoro-1-butyl,4-fluoro-2-butyl, 3-fluoromethyl-2-propyl, 1,1-di(fluoromethyl)ethyl,5-fluoro-1-pentyl, 6-fluoro-1-hexyl, hydroxymethyl, 2-hydroxyethyl,1-hydroxyethyl, 2-hydroxy-1-propyl, 2,3-dihydroxy-1-propyl,4-hydroxy-1-butyl, 5-hydroxy-1-pentyl, 6-hydroxy-1-hexyl or the like.

The term “alkoxy” includes, for example, straight chain or branchedchain C₁-C₆ alkoxy, in particular methoxy, ethoxy, n-propoxy, 2-propoxy,n-butoxy, 1,1-dimethylethoxy, n-pentyloxy, n-hexyloxy or the like.

A substituent of the “substituted alkoxy” includes, for example, asubstituent on the substituted alkyl.

The term “halogen-substituted alkoxy” includes, for example, straightchain or branched chain C₁-C₆ alkoxy substituted by 1 to 3 of halogenatom(s) such as fluorine, chlorine, bromine or the like, in particularfluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy,bromomethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy or thelike.

The term “alkylamino” includes, for example, amino substituted bystraight chain or branched chain C₁-C₆ alkyl, in particular methylamino,ethylamino, n-propylamino, 2-propylamino, n-butylamino, 2-butylamino,1-methylpropylamino, 1,1-dimethylethylamino, n-pentylamino, n-hexylaminoor the like.

The term “dialkylamino” includes, for example, amino substituted by twostraight chain or branched chain C₁-C₆ alkyls, in particulardimethylamino, diethylamino, ethylmethylamino, di-n-propylamino,di-n-butylamino or the like.

The term “halogen atom” includes, for example, fluorine, chlorine,bromine and iodine, preferably fluorine, chlorine or bromine.

The term “cycloalkyl” includes, for example, C₃-C₈ cycloalkyl, inparticular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like.

A substituent of the “substituted cycloalkyl” includes, for example,alkyl, alkoxy, hydroxy or the like.

The term “cycloalkylalkyl” includes, for example, straight chain orbranched chain C₁-C₆ alkyl substituted by C₃-C₈ cycloalkyl, inparticular cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl,cyclohexylmethyl, cyclohexylpropyl or the like.

The term “alkoxycarbonyl” includes, for example, straight chain orbranched chain C₁-C₆ alkoxycarbonyl, in particular methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, 2-propoxycarbonyl, n-butoxycarbonyl,2-butoxycarbonyl, 1-methylpropoxycarbonyl, 1,1-dimethylethoxycarbonyl,n-pentyloxycarbonyl, n-hexyloxycarbonyl or the like.

The term “alkanoyl” includes, for example, straight chain or branchedchain C₁-C₇ alkanoyl, in particular formyl, acetyl, propanoyl, butanoyl,pentanoyl, pivaloyl, hexanoyl, heptanoyl or the like.

A substituent of the “substituted alkanoyl” includes, for example, thesubstituent of the substituted alkyl, preferably hydroxy, alkoxy, cyclicimino, carboxy, alkoxyalkoxy, carboxyalkoxy, alkoxycarbonyl,alkanoyloxy, aryloxy, aryl, arylcarbonylamino, acylamino, amino, mono-or di-(alkyl)amino, arylalkylamino, aroylamino, alkanoylamino,alkylthio, halogen atom or the like. More preferable substituentincludes hydroxy, alkoxy, dialkylamino, morpholino, carboxy or the like.The substituted alkanoyl may be substituted by 1 to 3, preferably 1 to2, substituent(s) randomly selected from these groups.

The term “alkylcarbamoyl” includes, for example, straight chain orbranched chain C₁-C₆ alkyl substituted carbamoyl, in particularmethylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, 2-propylcarbamoyl,n-butylcarbamoyl, 2-butylcarbamoyl, 3-methyl-2-propylcarbamoyl,1,1-dimethylethylcarbamoyl, n-pentylcarbamoyl, n-hexylcarbamoyl or thelike.

The term “dialkylcarbamoyl” includes, for example, carbamoyl substitutedby two straight chain or branched chain C₁-C₆ alkyls, in particulardimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl,di-n-propylcarbamoyl, di-n-butylcarbamoyl or the like.

The term “alkylthio” includes, for example, straight chain or branchedchain C₁-C₆ alkylthio, in particular methylthio, ethylthio,n-propylthio, 2-propylthio, n-butylthio, 2-butylthio,1-methylpropylthio, 1,1-dimethylethylthio, n-pentylthio, n-hexylthio orthe like.

The term “alkylsulfinyl” includes, for example, straight chain orbranched chain C₁-C₆ alkylsulfinyl, in particular methylsulfinyl,ethylsulfinyl, n-propylsulfinyl, 2-propylsulfinyl, n-butylsulfinyl,2-butylsulfinyl, 1-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl,n-pentylsulfinyl, n-hexylsulfinyl or the like.

The term “alkylsulfonyl” includes, for example, straight chain orbranched chain C₁-C₆ alkylsulfonyl, in particular methylsulfonyl,ethylsulfonyl, n-propylsulfonyl, 2-propylsulfonyl, n-butylsulfonyl,2-butylsulfonyl, 1-methylpropylsulfonyl, 1,1-dimethylethylsulfonyl,n-pentylsulfonyl, n-hexylsulfonyl or the like.

The term “alkylsulfamoyl” includes, for example, straight chain orbranched chain C₁-C₆ alkylsulfamoyl, in particular methylsulfamoyl,ethylsulfamoyl, n-propylsulfamoyl, 2-propyl sulfamoyl, n-butylsulfamoyl,2-butylsulfamoyl, 1-methylpropylsulfamoyl, 1,1-dimethylethylsulfamoyl,n-pentylsulfamoyl, n-hexylsulfamoyl or the like.

The term “dialkylsulfamoyl” includes, for example, sulfamoyl substitutedby two straight chain or branched chain C₁-C₆ alkyls, in particulardimethylsulfamoyl, diethylsulfamoyl, ethylmethylsulfamoyl,di-n-propylsulfamoyl, di-n-butylsulfamoyl or the like.

The term “alkylaminothiocarbonyl” includes, for example, straight chainor branched chain C₁-C₆ alkyl substituted aminothiocarbonyl, inparticular methylaminothiocarbonyl, ethylaminothiocarbonyl,n-propylaminothiocarbonyl, n-butylaminothiocarbonyl,n-pentylaminothiocarbonyl, n-hexylaminothiocarbonyl or the like.

The term “alkylene” includes, for example, straight chain or branchedchain C₁-C₆ alkylene, in particular methylene, ethylene, trimethylene,tetramethylene, pentamethylene, methylethylene, 2-methyltrimethylene,2,2-dimethyltrimethylene, hexamethylene or the like. A preferableexample of the “alkylene” in Y² includes straight chain or branchedchain C₂-C₆ alkylene, more preferably straight chain or branched chainC₂-C₄ alkylene, particularly ethylene, trimethylene.

A substituent of the “substituted alkylene” includes, for example,hydroxy, alkoxy, halogen atom, amino, alkanoylamino or the like, and maybe substituted by 1 to 3, preferably 1 to 2, substituent(s) randomlyselected from these groups. Specific substituted alkylene includes2-hydroxytrimethylene or the like.

The term “alkenylene” includes, for example, straight chain or branchedchain C₃-C₆ alkenylene, in particular propenylene, butenylene,2-butenylene, pentenylene, 2-pentenylene, 3-pentenylene or the like.

The term “aryl” includes, for example, C₆-C₁₀ aryl, in particularphenyl, naphthyl or the like, preferably phenyl.

A substituent of the “substituted aryl” includes, for example, alkyl,alkoxy, halogen-substituted alkoxy, hydroxy, cyclic imino, monocyclicheterocycle, halogen atom, carboxy, cyano, amino, mono- ordi-(alkyl)amino, nitro, alkyl substituted by halogen atom or hydroxy,cycloalkyl, cycloalkylalkyl, methylenedioxy, ethylenedioxy,alkoxycarbonyl, carbamoyl, mono- or di-(alkyl)carbamoyl, alkylthio,alkylsulfinyl, alkylsulfonyl, sulfamoyl, alkylsulfamoyl,dialkylsulfamoyl, aryl, aryl substituted by a group selected from alkyl,alkoxy, halogen atom and hydroxy as a substituent or the like. Apreferable substituent includes alkyl, alkoxy, halogen-substitutedalkoxy, hydroxy, cyclic imino, monocyclic heterocycle, halogen atom,alkyl substituted by halogen atom or hydroxy, methylenedioxy or thelike, more preferably alkyl, alkoxy, halogen-substituted alkoxy,hydroxy, cyclic imino, halogen atom, methylenedioxy or the like. Apreferable example of a substituent of the “substituted aryl” in R¹, R²and R³ includes alkoxy, di(alkyl)amino, halogen-substituted alkoxy,cyclic imino, halogen atom, alkyl substituted by halogen atom orhydroxy, methylenedioxy or the like, more preferably C₁-C₄ alkoxy,trifluoromethoxy, morpholino, halogen atom, methylenedioxy or the like.The aryl may be substituted by the same or different 1 to 3, preferably1 to 2, substituent(s).

The term “aryl substituted by a group selected from alkyl, alkoxy,halogen atom or hydroxy as a substituent” includes, for example, C₆-C₁₀aryl (e.g. phenyl, naphthyl) substituted by one or more substituent(s),preferably the same or different 1 to 3, more preferably 1 to 2substituent(s) selected from a group consisting of straight chain orbranched chain C₁-C₆ alkyl such as methyl, ethyl, n-propyl, 2-propyl,n-butyl, 2-butyl, 1-methylpropyl, 1,1-dimethylethyl, n-pentyl orn-hexyl, straight chain or branched chain C₁-C₆ alkoxy such as methoxy,ethoxy, propoxy, 2-propoxy, n-butoxy, 1,1-dimethylethoxy, n-pentyloxy orn-hexyloxy, halogen atom such as fluorine, chlorine, bromine or iodine,and hydroxy. In particular, 4-methylphenyl, 2-methylphenyl,4-(n-propyl)phenyl, 4-(2-propyl)phenyl, 4-(n-butyl)phenyl,4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,4-ethoxyphenyl, 4-(n-propoxy)phenyl, 4-(n-butoxy)phenyl, 4-bromophenyl,4-fluorophenyl, 3,4-difluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl,2-hydroxyphenyl or the like are included.

The term “cyclic imino” includes, for example, 5- or 6-membered cyclicimino optionally containing additional oxygen atom or nitrogen atom as aring-forming heteroatom, in particular pyrrolidino, piperidino,morpholino or the like. In cyclic imino for —N(R⁶)R⁷, a 5- or 6-memberedcyclic imino optionally containing additional oxygen atom or nitrogenatom as a ring-forming heteroatom may be optionally fused to benzenering. An example of such cyclic imino includes, for example,benzopiperidino, benzopyrrolidinyl, benzomorpholino or the like.

The term “monocyclic heterocycle” includes, for example, 5- or6-membered heterocycle containing 1 to 3 heteroatom(s) selected fromnitrogen atom, oxygen atom and sulfur atom, provided that theheterocycle does not contain simultaneously both of oxygen atom andsulfur atom, in particular aromatic heterocycle such as thienyl, furyl,pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, or non-aromaticheterocycle such as dioxolanyl, pyranyl or dioxanyl. Preferably, theheterocycle includes aromatic heterocycle, particularly pyridyl.

The term “bicycle heterocycle” includes, for example, fused heterocyclewherein a 5- or 6-membered heterocycle containing 1 to 3 heteroatom(s)selected from nitrogen atom, oxygen atom and sulfur atom is fused to abenzene ring, provided that the heterocycle does not containsimultaneously both of oxygen atom and sulfur atom, in particularbenzofuryl, benzothienyl, indolyl, isoindolyl, indazolyl, quinolyl,isoquinolyl, quinazolyl, phthalazinyl, quinoxalinyl or the like.

A substituent of the “substituted monocyclic heterocycle” and“substituted bicyclic heterocycle” includes, for example, alkyl, alkoxy,halogen atom, hydroxy or the like. The monocyclic heterocycle may besubstituted by the same or different 1 to 3, preferably 1 to 2,substituent(s) as mentioned above.

The term “aroyl” includes, for example, C₇-C₁₁ aroyl, in particularbenzoyl, naphthoyl or the like.

The term “prodrug” refers to a compound which is hydrolyzed in vivo toregenerate a 5-membered ring compound of the present invention. Theprodrug of the present invention includes any compounds preparedaccording to any procedures for making a prodrug known to those skilledin the art. For example, in case that a 5-membered ring compound of thepresent invention has carboxyl group, amino group or the like, a prodrugcorresponds to a compound wherein these groups are induced to estergroup, amide group or the like which can be easily hydrolyzed in vivo.In case that a 5-membered ring compound has carboxyl group, a prodrugincludes a compound wherein the carboxyl group is converted into esterswith alkyl (e.g. methyl or ethyl), alkyloxyalkyl (e.g. methyloxymethyl,ethyloxymethyl, 2-methyloxyethyl or 2-methyloxyethyloxymethyl),acyloxymethyl (e.g. pivaloyloxymethyl, acetyloxymethyl,cyclohexylacetyloxymethyl or 1-methylcyclohexylcarbonyloxymethyl),alkoxycarbonylalkyl (e.g. ethyloxycarbonyloxy-1-ethyl), andcycloalkyloxycarbonylalkyl (e.g. cyclohexyloxycarbonyloxy-1-ethyl). Incase that a 5-membered ring compound has amino group, a prodrug includesa compound wherein the amino group is converted into acetamide group.

The 5-membered ring compound of the present invention of the formula (1)can be a pharmaceutically acceptable salt thereof. The pharmaceuticallyacceptable salt includes an acid addition salt and a base addition salt.The acid addition salt includes, for example, an inorganic acid saltsuch as hydrochloride, hydrobromide, sulfate, and an organic acid saltsuch as citrate, oxalate, malate, tartrate, fumarate, maleate, and thebase addition salt includes an inorganic base salt such as sodium salt,calcium salt, and an organic base salt such as meglumine salt,trishydroxymethylaminomethane salt.

The compound of the present invention may optionally have anasymmetrical center or a substituent having a chiral carbon, and opticalisomers may exist. The present invention includes a racemic mixture ofthese optical isomers and isolated optical isomers. The presentinvention includes a solvate such as a hydrate of a 5-membered ringcompound or a pharmaceutically acceptable salt thereof.

The 5-membered ring compound or a pharmaceutically acceptable saltthereof, or a pharmaceutically acceptable prodrug, and a pharmaceuticalcomposition thereof are useful as an agent for preventing and/ortreating a chronic obstructive pulmonary disease.

The 5-membered ring compound has an action in a different mechanism fromthat of existing agents, and hence it can be used in a combination withany existing agent which has been used for preventing and/or treatingthe above disease. For example, the compound can be combined withantiallergic agent (e.g. chemical mediator release inhibitor,antihistamine agent, antileukotriene agent, antithromboxane agent or Th2cytokine inhibitor), steroid drug (e.g. inhaled steroid drug, nasalsteroid drug or internal steroid drug), immunosuppressant (e.g.cyclosporine, tacrolimus hydrate or pimecrolimus), xanthinebronchodilator (e.g. theophylline), bronchodilator or nasal dilator(e.g. β stimulant, sympathetic stimulant or parasympatholytic agent suchas anticholinergic agent), vaccine therapeutic agent, gold drug, Chinesemedicine formulation, a combination of these drugs (e.g. a combinationof inhaled β stimulant with inhaled steroid drug), or the like.Especially, when it is used in a combination with steroid drug or asteroid mixture, it enhances the therapeutic effects of the steroid, andthereby it allows to reduce the amount of the steroid drugs or to omitthe use of steroid drugs.

The anticholinergic agent includes, for example, tiotropium bromide,ipratropium bromide, flutropium bromide and oxytropium bromide; theantiallergic agent includes, for example, cromoglycic acid, sodiumcromoglycate and tranilast; the antihistamine agent includes, forexample, diphenhydramine, chlorpheniramine, cetirizine, loratadine,diphenylpyraline, olopatadine, bepotastine, ketotifen, terfenadine,mequitazine, aselastine, epinastine, ozagrel, fexofenadine, ebastine andoxatomide; the antileukotriene agent includes, for example, pranlukastand montelukast; and the Th2 cytokine inhibitor includes, for example,suplatast.

The inhaled β stimulant includes, for example, salmeterol, procatechol,mabuterol, trimetoquinol, tubuterol, theophylline, salbutanol,preferably salmeterol. The steroid drug includes, for example,fluticasone, beclomethasone, prednisolone, dexamethasone, betamethasone,preferably fluticasone. The mixture of the inhaled β stimulant and theinhaled steroid drug includes, for example, a mixture of salmeterol andfluticasone.

The 5-membered ring compound, a pharmaceutically acceptable salt or apharmaceutically acceptable prodrug thereof and a pharmaceuticalcomposition thereof can be orally or parenterally administered. They canbe administered in conventional dosage forms when orally administered.They can be parenterally administered in a dosage form such as topicalpreparations (e.g. inhalants, nasal preparations and externalpreparations), injections, transdermal preparations, or transnasalpreparations. The oral preparations and rectal preparations include, forexample, capsules, tablets, pills, powders, cachets, suppositories andliquid preparations. The injections include, for example, sterilesolutions or suspensions. The topical preparations include, for example,creams, ointments, lotions and transdermal preparations such as adhesivepreparations.

The above dosage form may be formulated in a conventional manner using apharmaceutically acceptable excipient or additive. The excipient oradditive includes, for example, carrier, binder, flavoring agent,buffering agent, thickening agent, coloring agent, stabilizer,emulsifier, dispersing agent, suspending agent and antiseptic agent. Thecarrier includes, for example, magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectine, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, low melting wax andcocoa butter.

The capsule can be prepared by capsulating a 5-membered ring compound,or a pharmaceutically acceptable salt or a pharmaceutically acceptableprodrug thereof together with a pharmaceutically acceptable carriercombining with or without a pharmaceutically acceptable excipient. Thecachet can be also prepared in the similar manner.

The powder may be formulated together with a base for a pharmaceuticallyacceptable powder. The base includes talc, lactose and starch. A dropcan be formulated by combining an aqueous or nonaqueous base with one ormore pharmaceutically acceptable diffusing agent, suspending agent,solubilizer or the like.

A liquid preparation for injection includes solution, suspension andemulsion. Such preparation includes, for example, an aqueous solutionand aqueous propylene glycol solution. The liquid preparation mayoptionally contain water. It can be also prepared in the form of asolution of polyethyleneglycol and/or propylene glycol. The liquidpreparation suitable for oral administration can be prepared by adding a5-membered ring compound, or a pharmaceutically acceptable salt or apharmaceutically acceptable prodrug thereof to water, if necessary,together with coloring agent, flavoring agent, stabilizing agent,sweetening agent, solubilizer or thickening agent. Also, the liquidpreparation suitable for oral administration can be prepared by adding a5-membered ring compound, or a pharmaceutically acceptable salt or apharmaceutically acceptable prodrug thereof to water with a dispersingagent to improve its viscosity. A thickening agent includes, forexample, a pharmaceutically acceptable natural or synthetic rubber,resin, methylcellulose, sodium carboxymethylcellulose or a knownsuspending agent.

The topical preparation includes the above liquid preparation, cream,aerosol, spray, powder, lotion and ointment. The above topicalpreparation can be prepared by combining a 5-membered ring compound, ora pharmaceutically acceptable salt or a pharmaceutically acceptableprodrug with a conventional pharmaceutically acceptable diluent andcarrier. The ointment and cream may be obtained by adding thickeningagent and/or gelling agent to aqueous or oily base to be formulated. Thebase includes, for example, water, liquid paraffin and vegetable oil.The thickening agent includes, for example, soft paraffin, aluminumstearate, cetostearyl alcohol, propylene glycol, lanolin, hydrogenatedlanolin and bees wax. The lotion can be prepared by adding one or morepharmaceutically acceptable stabilizing agent, suspending agent,emulsifier, diffusing agent, thickening agent, coloring agent orflavoring agent to aqueous or oily base. The topical preparation mayoptionally contain antiseptic agent or antiproliferating agent forbacteria such as methyl hydroxybenzoate, propyl hydroxybenzoate,chlorocresol or benzalkonium chloride, if necessary. A 5-membered ringcompound, or a pharmaceutically acceptable salt or a pharmaceuticallyacceptable prodrug thereof can be also administered in a dosage formsuch as liquid preparation spray, powder, dry powder or drop preparationas transpulmonary preparation or inhalant, or transnasal or nasalpreparation. Also, liquid preparation or suspension can be used aseye-drops.

A dose or the number of administration of the compound of the presentinvention depends on conditions, ages, weights, dosage form or the like.In oral administration, the compound of the present invention can beusually administered in the range of about 1 to about 1000 mg,preferably about 2 to about 500 mg, particularly about 5 to about 200 mgper day for adults at one time or by dividing for several times. Ininjections, the compound of the present invention can be intravenouslyadministered in the range of about 0.1 to about 300 mg, preferably about1 to about 200 mg at one time or by dividing for several times orcontinuously. In transpulmonary preparation or inhalant, or transnasalor nasal preparation, the compound of the present invention can beadministered in the range of about 0.1 to about 300 mg, preferably about1 to about 200 mg at one time or by dividing for several times. Inexternal preparation such as ointment or cream, the compound of thepresent invention can be applied in the range of about 0.1 to about 300mg, preferably about 1 to about 200 mg at one time or by dividing forseveral times. In adhesive preparation; the compound of the presentinvention can be patched in the range of about 0.1 to about 300 mg,preferably about 1 to about 200 mg at one time or by dividing forseveral times.

Examples by which the present inventors have accomplished the presentinvention are described in detail below, but the present invention isnot intended to be limited to these examples.

(Test Drug)

Theophylline purchased from Sigma-Aldrich was used.

EXAMPLES Example 1

N-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholinophenyl)-thiazol-3(2H)-yl]ethyl}-N′-methylurea(SMP-028)

(1) To a solution of acetonitrile (20 ml) containing t-butyl2-(aminoethyl)carbamate (1.02 g) was added dropwise3-fluorophenylisothiocyanate (752 mg), and the mixture was heated at 75°C. for 1 hour. The reaction mixture was concentrated in vacuo,crystallized from n-hexane to give t-butyl2-{[(3-fluoroanilino)carbothioyl]amino}ethylcarbamate (1.81 g).

¹H-NMR (CDCl₃): δ1.35 (9H, s), 3.35 (2H, m), 3.74 (2H, m), 4.89 (1H,bs), 6.99 (3H, m), 7.37 (1H, m), 7.81 (1H, bs)

(2) A mixture of t-butyl2-{[(3-fluoroanilino)carbothioyl]amino}ethylcarbamate (1.81 g) obtainedin above (1), β-bromo-4′-morpholinoacetophenone (1.56 g) and ethanol (20ml) was stirred to heat at 45° C. under nitrogen atmosphere. After 1hour, the resulting crystal was filtered to give tert-butyl{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholinophenyl)thiazol-3(2H)-yl]ethyl}carbamate(1.76 g). A mixture of the resulting compound (1.76 g), methanol (5 ml)and a solution of 4N-hydrogen chloride dioxane (50 ml) was stirred atroom temperature. After 3 hours, the reaction mixture was concentratedin vacuo, and an insoluble solid was filtered off to giveN-[3-(2-aminoethyl)-4-(4-morpholinophenyl)thiazol-2(3H)-ylidene]-3-fluoroaniline(1.57 g). To a mixture of the resulting compound (1.57 g), an aqueous2N-sodium hydroxide solution (10 ml) and tetrahydrofuran (20 ml) wasadded phenyl N-methylcarbamate (907 mg), and the mixture was stirred toheat at 55° C. After 3 hours, to a reaction mixture was added water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and then dried over sodium sulfate, and the solventwas removed in vacuo. The residue was crystallized from methanol to givethe titled compound (810 mg) as needles.

Data for 2θ in powder X-ray crystallographic analysis are shown below.Also, a corresponding figure is shown in FIG. 1.

2θ Relative intensity 5.8 34 11.5 40 13.3 23 16.7 100 18.7 17 19.0 3120.3 15 22.1 15 24.1 15 24.5 27 26.0 18

Melting point: 190-191° C.

IR (KBr, cm⁻¹): 3328, 2949, 2852, 1618, 1595, 1577.

¹H-NMR (CDCl₃): δ2.69 (3H, d, J=4.8), 3.26 (4H, t, J=4.8), 3.45 (2H, m),3.89-3.93 (6H, m), 5.10-5.60 (2H, m), 5.80 (1H, s), 6.80-6.93 (3H, m),6.97 (2H, d, J=8.8), 7.28-7.54 (3H, m).

Example 2N-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholinophenyl)-thiazol-3(2H)-yl]ethyl}-N′-methylurea salt (1) Synthesis ofN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureahydrobromide

To a suspension ofN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylurea(455 mg) in chloroform (50 ml) was added 25% HBr/AcOH (0.32 g), and themixture was stirred to dissolve for 30 minutes. The solvent was removed,and then thereto was added diethylether and a precipitate was filteredto give crystals (520 mg) of which a melting point was 191 to 193° C.

(2) Synthesis ofN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureabenzenesulfonate

Crystals (610 mg) of which a melting point was 153.5 to 156° C. wasobtained using benzenesulfonic acid (158 mg) according to the sameprocedure as mentioned above.

(3) Synthesis ofN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureahydrochloride

Crystals (488 mg) of which a melting point was 188 to 189° C. wasobtained using a solution (0.25 ml) of 4N hydrochloride dioxaneaccording to the same procedure as mentioned above.

(4) Synthesis ofN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureahydrosulfate

Crystals (530 mg) of which a melting point was 203 to 204° C. wasobtained using hydrosulfuric acid (98 mg) according to the sameprocedure as mentioned above.

(5) Synthesis ofN-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl]ethyl}-N′-methylureamethanesulfonate

Crystals (530 mg) of which a melting point was 206 to 207.5° C. wasobtained using methanesulfonic acid (96 mg) according to the sameprocedure as mentioned above.

Example 3N-{2-[2-[(3-fluoro-4-hydroxyphenyl)imino]-4-(4-morpholinophenyl)-thiazol-3(2H)-yl]ethyl}-N′-methylurea

(1) To a solution of 4-amino-2-fluorophenol in toluene was added phenylchlorothionoformate, and after 30 minutes thereto was added an aqueous1N sodium hydroxide solution. The mixture was stirred for 3 hours atroom temperature, and then thereto was added t-butyl2-(aminoethyl)carbamate, and the mixture was stirred overnight to givet-butyl 2-{[(3-fluoro-4-hydroxyanilino)carbothioyl]amino}ethylcarbamate.(2) The titled compound was obtained using t-butyl2-{[(3-fluoro-4-hydroxyanilino)carbothioyl]amino}ethylcarbamate obtainedin above (1) and α-bromo-4′-morpholinoacetophenone according to thesimilar procedure to Example 1.

¹H-NMR (DMSO-d6): δ2.46 (3H, d, J=4.7), 3.17-3.24 (6H, m), 3.72-3.76(6H, m), 6.01 (1H, s), 6.63-6.66 (1H, m), 6.75-6.78 (1H, m), 6.87-6.93(1H, m), 6.99 (2H, d, J=8.85), and 7.29 (2H, d, J=8.85).

Example 4N-{2-[2-[(3-fluorophenyl)imino]-4-[4-(2-hydroxyethyl)aminophenyl)-thiazol-3(2H)-yl]ethyl}-N′-methylurea

Starting from 3-[4-(bromoacetyl)phenyl]-1,3-oxazolin-2-one obtained byreacting 3-(4-acetylphenyl)-1,3-oxazolin-2-one with equal quantity ofpyridinium tribromide in chloroform according to the similar procedureto Example 1 gaveN-{2-[2-[(3-fluorophenyl)imino]-4-[4-(2-oxo-1,3-oxazolin-3-yl)phenyl]-thiazol-3(2H)-yl]ethyl}-N′-methylurea,and the resulting compound was added to an aqueous solution of 4N sodiumhydroxide in methanol, and the mixture was heated to 50° C. After 2hours, the mixture was standing to cool and the solvent was removed. Toa residue was added methanol, and an insoluble was filtered off andmethanol was removed. A residue was recrystallized from methanol,2-propanol to give the titled compound.

¹H-NMR (DMSO-d6): δ2.59 (3H, d, J=4.6), 3.24 (2H, q, J=5.9), 3.36 (2H,q, J=6.3), 3.68 (2H, q, J=5.9), 4.84 (2H, t, J=6.4), 4.83 (1H. t,J=5.4), 5.77 (1H, d, J=4.5), 6.04-6.10 (3H, m), 6.74 (2H, d, J=8.6),6.89-6.98 (3H, m), 7.26 (2H, d, J-8.6), 7.28-54 (1H, m).

Example 5N-{2-[2-[(3-fluorophenyl)imino]-4-(4-morpholinophenyl)-thiazol-3(2H)-yl]ethyl}-urea

N-[3-(2-aminoethyl)-4-(4-morpholinophenyl)thiazol-2(3H)-ylidene]-3-fluoroanilineobtained in Example 1 was dissolved in THF, and thereto was addedtriethylamine, and then thereto was added 4-nitrophenyl chloroformateunder ice-cooling. The mixture was stirred for 2 hours. Thereto wasadded ammonia water, and the mixture was stirred for 2 hours at roomtemperature. The resulting compound was recrystallized from methanol togive the titled compound.

¹H-NMR (CDCl₃): δ3.26 (4H, t, J=4.9), 3.45 (2H, t, J=5.7), 3.89-3.94(6H, m), 5.79 (1H, s), 6.77-6.90 (3H, m), 6.97 (2H, d, J=8.8), 7.27-7.34(3H, m).

Example 6 Effects of the Drug on Guinea Pig Chronic ObstructivePulmonary Disease (COPD) Model (1) A Guinea Pig Chronic ObstructivePulmonary Disease (COPD) Model

An evaluation was carried out as follows according to a report of KosukeMORIZUMI, Junichi FUCHIGAMI et al., 2002, The 75th Annual Meeting of theJapanese Pharmacological Society (2002) Abstract No. P-259, “Study of achronic obstructive pulmonary disease-Effects of theophylline onrespiratory function and lung function of guinea pigs in an exposure ofcigarette smoke.”

Male Hartley strain guinea pigs (purchased from Japan SLC, Inc.) weretaken in a cigarette exposure holder (RMH-TUBES, manufactured byMuenster Ltd.) to secure them to an exposure chamber (Flow-past typenose-only inhalation chamber, manufactured by Muenster Ltd.), andallowed to inhale cigarette smoke (Hi-Lite, manufactured by JapanTobacco Inc.) for 60 minutes per day for 5 days in a week, totally 4weeks using a smoking exposure equipment (Hamburg II, manufactured byBorgwaldt Technik), while the exposure was carried out for 4 days in the4th week.

(2) Drug Administrations

Each 0.5% MC suspension of a test drug was orally administered daily in5 ml/weight (kg) once a day for 25 days from the first day of theexposure. To a sham-exposure group and a control group was orallyadministered a 0.5% MC suspension in a similar manner. Any oraladministrations were carried out 0.5 to 1 hours before exposures on acigarette-smoke-exposure day or after measurements when measuringrespiratory functions. A drug was not administered on the day formeasurement of respiratory functions after finishing the 4th week of theexposure.

(3) Measurements of Airway Resistance

Specific airway resistances (sRaw) in guinea pigs were measured duringawakening by double-flow plethysmography using general respiratoryfunction analysis system (PULMOS-I, manufactured by M•I•P•S Corp.).Measurements were carried out before the exposure and on the day afterfinishing the 1st, 2nd, 3rd and 4th weeks of the exposure. Each 100breathings of respiratory functions were individually measured, and theaverage values were obtained as measured values. A rate of change ofairway resistances was calculated by the following equation.

Rate of change of each measured week (%)=100×(a measured value on eachmeasured date−a measured value before starting exposures of cigarettesmoke)/a measured value before starting exposures of cigarette Smoke

Results are shown in Table 1.

TABLE 1 Effects of the drug on airway resistance (sRaw) changes inguinea pig COPD model Specific airway resistance (sRaw) Dose % increasefrom pre value Groups (mg/kg/day) 1 week 2 weeks 3 weeks 4 weekssham-exposure — 4.97^(NS) ± 3.33    3.24^(##) ± 6.28  10.20^(##) ±7.19   19.41^(#) ± 5.26   control  0 22.16 ± 8.94  52.17 ± 11.23 57.02 ±13.54 63.92 ± 13.47 SMP-028 10 25.54 ± 10.91 41.45^(NS) ± 13.12   40.60^(NS) ± 12.74    51.31^(NS) ± 14.54    SMP-028 30 15.02 ± 4.07 24.29^(NS) ± 8.56     34.82^(NS) ± 6.34     38.96^(NS) ± 5.17    theophylline 10 15.02 ± 6.73  21.66^(NS) ± 9.32     22.94^(NS) ±10.43    31.26^(NS) ± 10.60    Guinea pigs were exposed to cigarettesmoke for 60 min per day, for 5 days per week, for 4 weeks (4 days inlast week). Each value represents mean ± SEM of 8 animals. ^(#)p < 0.05,^(##)p < 0.01 vs. control (Student's t-test or Aspin-Welch test).^(NS)not significant vs. control (Dunnett's test for SMP-028 orStudent's t-test for theophylline).

(4) Measurements of Lung Functions

After measuring airway resistances in the 4th week, animals were cutopen their tracheas under urethane-anesthetizing (1.6 mg/kg, i.p.),cannulated on the side of lung, fixed by ligation, and measured residualvolumes (RV) and functional residual capacities (FRC) by lung functionsmeasuring system (Biosystem for maneuver, manufactured by BuxcoElectronics).

Results are shown in Table 2.

TABLE 2 Effects of the drug on changes of functional residual capacity(FRC) and residual volume (RV) in guinea pig COPD model Functionalresidual Residual volume Dose capacity (FRC) (RV) Groups (mg/kg/day)(mL) (mL) sham-exposure — 6.049 ± 0.343^(##) 1.906 ± 0.366^(##) control 0 7.966 ± 0.223 3.262 ± 0.188 SMP-028 10 7.213 ± 0.374^(NS) 3.236 ±0.537^(NS) SMP-028 30 7.066 ± 0.353^(NS) 2.649 ± 0.649^(NS) theophylline10 6.916 ± 0.234** 1.962 ± 0.417* Each value represents mean ± SEM of 8animals. ^(##)p < 0.01 vs. control (Student's t-test). *p < 0.05, **p <0.01 vs. control (Student's t-test). ^(NS)not significant vs. control(Dunnett's test).

(5) Measurements of Inflammatory Cells in Bronchoalveolar Fluid

After measuring lung functions, animals were exsanguinated to death andopened the thorax, ligated the left bronchial bifurcation, and theninjected saline (2.5 mL) into the right lung and aspirated the same viafixed cannula on measuring lung functions repeatedly in twice (totally 5mL), and the recovery solution was obtained as a bronchoalveolar lavagefluid (BALF). BALF was centrifuged (230×g, 4° C., for 10 minutes) togive cell pellets. The pellets were suspended in saline (0.5 mL), and toa part of the suspension was added Türk solution (manufactured by WakoPure Chemical Industries, Ltd.) so as to dilute 10 to 20 folds.Leukocyte numbers per 0.1 μL were measured by a blood cell countingchamber and leukocyte numbers per 1 μL were calculated. Cell suspensionswere prepared again, smears were prepared using about 2000 to 3000 totalcell numbers, May-Grunwald-Giemsa stain was carried out, leukocytenumbers were counted under the microscope, a ratio of each leukocytenumber to total leukocyte number was obtained, and each cell number per1 μL was calculated based on the ratio. Results are shown in each cellnumber per 1 μL.

The results are shown in Table 3.

TABLE 3 Effects of the drug on changes of leukocyte numbers inbronchoalveolar fluid in guinea pig COPD model Dose (mg/ kg/ Cell numberin BALF (cells/μL) Group day) Total Macrophage Neutrophil sham- — 2134 ±239^(##) 1677 ± 196^(##)  65 ± 24^(##) exposure control  0 5484 ± 14043365 ± 259 1220 ± 187 SMP-028 10 4044 ± 419^(NS) 2506 ± 313^(NS) 1114 ±193^(NS) SMP-028 30 3897 ± 783^(NS) 2497 ± 483^(NS)  772 ± 277^(NS)theophyl- 10 3578 ± 583* 2068 ± 362* 1072 ± 322^(NS) line Each valuerepresents mean ± SEM of 8 animals. ^(##)p < 0.01 vs. control (Student'st-test or Aspin-Welch test). *p < 0.05 vs. control (Student's t-test).^(NS)not significant vs. control (Dunnett's test for SMP-028 orStudent's t-test for theophylline).

(6) Histological Investigations

After collection of BALF, trachea and lung were isolated. The ligationsite of the left lung was opened, injected neutral formalin buffer intotrachea, bronchi and lung at the pressure of 20 cm H₂O via cannula fixedon the side of the lung, and the lung tissue was extended to be fixed.According to a conventional method, tissue section samples were producedusing posterior lobe of the left lung and hematoxylin-eosin (HE) stainwas carried out. Any other lung tissues were stored in neutral formalinbuffers. Drug efficacies of the produced tissue samples were evaluatedby scoring tissue changes under the microscope. The criteria of scoreswere shown as follows: −: none, ±: minimal, +: mild, ++: moderate, +++:severe. Each quantification was calculated as 0, 1, 2, 3, 4.

Results are shown in Table 4 and FIG. 2.

TABLE 4 Effects of the drug on pathological finding changes of lung inguinea pig COPD model Group and dose SMP-028 10 mg/kg/day sham-exposurecontrol for 25 days Number of animals 8 8 8 Grade Findings − ± + ++ +++− ± + ++ +++ − ± + ++ +++ A. 8 0 0 0 0 NS 7 1 0 0 0 7 1 0 0 0 B. 8 0 0 00 NS 7 1 0 0 0 7 1 0 0 0 C. 8 0 0 0 0 ## 1 3 4 0 0 4 2 2 0 0 NS D. 8 0 00 0 ## 1 3 4 0 0 3 3 2 0 0 NS E. 8 0 0 0 0 NS 8 0 0 0 0 8 0 0 0 0 Groupand dose SMP-028 theophylline 30 mg/kg/day 10 mg/kg/day for 25 days for25 days Number of animals 8 8 Grade Findings − ± + ++ +++ − ± + ++ +++A. 8 0 0 0 0 7 1 0 0 0 B. 8 0 0 0 0 8 0 0 0 0 C. 5 2 1 0 0 NS 7 0 1 00 * D. 3 3 2 0 0 NS 6 1 1 0 0 * E. 8 0 0 0 0 7 1 0 0 0 Findings A.Hyperplasia, epithelial cell, bronchus B. Cellular exudation,neutrophil/eosinophil, lumen, bronchiole C. Thickening, alveolar wall D.Accumulation, foamy/macrophage-like cell, alveolus E. Cellularinfiltration, neutrophil, alveolus ## p < 0.01 vs. control (Wilcoxon'stest). * p < 0.05 vs. control (Wilcoxon's test). NS: not significant vs.control (Wilcoxon's test). NS: not significant vs. control (Steel test)Grade sign: −: none, ±: minimal, +: mild, ++: moderate, +++: severe.

(7) Evaluation Results

As is shown in Table 1, airway resistances of a control group (exposuregroup) were raised with time by cigarette smoking stimulation, andsignificantly increased relative to those of a sham-exposure group(non-exposure group) on the 2nd, 3rd, 4th week of cigarette smokeexposure. It was shown that the increases of airway resistance tended tobe suppressed in the groups of 10 mg/kg and 30 mg/kg of SMP-028.

As is shown in Table 2, functional residual capacity (FRC) and residualvolume (RV) of control group were significantly increased by cigarettesmoking stimulation relative to those of sham-exposure group. It wasshown that the increases of functional residual capacity (FRC) andresidual volume (RV) tended to be suppressed in the groups of 10 mg/kgand 30 mg/kg of SMP-028.

As is shown in Table 3, total cell numbers, macrophage and neutrophil incontrol group were infiltrated into trachea and lung by cigarettesmoking stimulation relative to those in sham-exposure group. It wasshown that the infiltrations of the inflammatory cells in the airwaytended to be suppressed in the groups of 10 mg/kg and 30 mg/kg ofSMP-028.

As is shown in Table 4, accumulation of foamy cells/macrophage-likecells within the alveoli and thickening of the alveolar wall bycigarette smoking stimulation were found in control group. Also, minimalhyperplasia of bronchial epithelium, and neutrophil/eosinophil exudateinto bronchiolar lumen were found. These findings are lung lesionssimilar to human chronic obstructive pulmonary disease. In thesepathological changes, it was shown that the accumulation of foamycells/macrophage-like cells within the alveoli and thickening of thealveolar wall tended to be suppressed in the groups of 10 mg/kg and 30mg/kg of SMP-028. The results of scoring these pathological findings areshown in FIG. 2. It was shown that the pathological findings tended tobe dose-dependently suppressed in SMP-028 relative to those in controlgroup.

It has been found that SMP-028 shows tendency of improving respiratoryfunction, lung function, alveolar destruction and inflammation andprevents progression of these lung lesions caused by smoking stimulationin the present model, and hence, SMP-028 is very useful for a method fortreating a chronic obstructive pulmonary disease.

Example 7 Inhibition Tests by Addition of Various CYP Inhibitors

Inhibition tests to various CYP are carried out using test compounds asfollows.

Inhibitors and Addition Concentrations

Furafylline (CYP1A2)  1 or 10 μM Sulfaphenazole (CYP2C9)  1 or 10 μMBenzylnilvanol (CYP2C19) 0.5 or 5 μM Quinidine (CYP2D6) 0.1 or 1 μMAzamurin (CYP3A4) 0.5 or 5 μM Montelukast (CYP2C8)  5 or 50 uM

Reaction System (Final Concentration)

Potassium phosphate buffer 50 mM (Kpi)(pH7.4) Human liver Ms 0.5 mg/mlSubstrate 1 μM Inhibitor 0, 0.1, 1, 5 or 10 μM (See above) NADPH 1 mMReaction liquid volume 250 μL Reaction time 15 min n = 2

Additive Amounts Per 1 Tube

500 mM Kpi (pH7.4)   25 μl 20 mg/ml human liver Ms 6.25 μl 5 mM NADPH  50 μl 1 mM substrate 0.25 μl 0.01, 0.1, 0.5, or 1 mM inhibitor  2.5 μlPurified water adjust to  250 μl

Methanol Containing Internal Standard (I.S.)

100 μl of I.S. 10 μg/ml is measured up to 100 ml with methanol.

5 mM NADPH (M.W. 745.43 Purity 82.9%)

NADPH is weighed to dissolve in ion-exchange water.

Experimental Procedure

Mixed solutions of Kpi, Microsome (Ms), substrate and purified waterexcept for NADPH of common components among the above components areprepared.

For 30 bottles Kpi 1000 μl Ms  250 μl Substrate  10 μl Purified water6640 μlPut the mixed solution (197.5 μl) into Eppendorf tube in which inhibitor(2.5 μl) is dispensed.

↓

A reaction is started by adding 5 mM NADPH (50 μl) to a tube for a 15min reaction.

↓

Incubation at 37° C. for 15 min.

↓

Quenching by addition of methanol containing I.S. (750 pp.

↓

To a sample in 0 min is added methanol containing I.S. (750 μl),followed by 5 mM NADPH (50 μl).

↓

Suction filtration by a filter plate.

↓

Analyzing by LC-MS/MS (No. 6, API4000). LC/MS/MS Analysis Condition

Carrier: 10 mM ammonium acetate buffer (pH4)/MeOH=A/B

Column: Inertsil 2.1*50 mm (3 um), 40° C.

Positive

Time (min) Flow (μl/min) A % B % 0.0 200 95 5 2.0 200 10 90 5.0 200 1090 5.1 200 95 5 8.0 200 95 5

Example 8 Effects of the Drug on Thyroid

C57BL/6 mice (Charles River, male, 6-week old) are received, and after 1week of quarantine term, normal animals are used in the experiment. Testcompounds suspended in 0.5% aqueous methylcellulose solutions (MC) (10mL/kg) are continuously orally administered once a day for 5 days.Dosages of test compounds are 30, 100 and 300 mg/kg. To a control groupis administered 0.5% MC in a similar manner. 9 hours after finaladministration, mice are treated to collect whole blood from heart underether-anesthetizing, and serums are separated using Separapid tubes.Separated serums are stored at −80° C. until T4 measurement. T4 ismeasured by using total thyroxine (T4) enzyme immunoassay test kit (ICNInc., Cat No. 07B90102).

Example 9 Subacute Toxicity Test Materials and Method

(1) Test compounds.(2) Animals: rats, Crj:CD(SD)IGS, male, 5-week old at the start ofadministration.(3) A method for preparing administration solutions: Test articles aresuspended in 0.5% MC solutions, and dilute solutions are sequentiallyprepared by using 0.5% MC solutions.(4) Administration route and method: Gavage administrations are carriedout by using disposable syringes and elasticity catheters once a day (inthe morning hours).

Observation, Measurement and Assessment:

a. During Dosing Period(i) General condition: All animals are observed once or more times a daythrough the dosing period.(ii) Weight: All animals are measured on the 1st, 4th, 8th and finaldate for administration, and further on the day of anatomy.(iii) Intake: An intake per cage for about continuous 48 hourscontaining a weight check date is measured once a week through thedosing period.b. At the End of the Dosing Period(i) Hematological assessment(ii) Blood biochemical assessment(iii) Organ weights

(iv) Necropsy

(v) Histopathological assessment

INDUSTRIAL APPLICABILITY

The method and the agent of the present invention can be safely appliedto a patient with a chronic obstructive pulmonary disease withoutadverse effects in administration at one time or by dividing for severaltimes per day, and are extremely excellent for preventing and/ortreating a chronic obstructive pulmonary disease.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1: FIG. 1 indicates powder X-ray crystallographic analysis of thecompound obtained as needles in Example 1.

FIG. 2: FIG. 2 indicates an effect of the drug on pathological findingchanges of lung in guinea pig COPD model in Example 6(6).

1. A method for preventing and/or treating a chronic obstructivepulmonary disease by administering a 5-membered ring compound of theformula (2):

or a pharmaceutically acceptable salt thereof in a dosage form selectedfrom oral administration, injection, transpulmonary preparation,inhalant, transnasal or nasal preparation, external preparation, oradhesive preparation, wherein the compound can be administered in oraladministration in the range of 2 to 500 mg per day for adults at onetime or by dividing for several times; the compound can be intravenouslyadministered in injections in the range of 1 to 200 mg at one time or bydividing for several times or continuously; the compound can beadministered in transpulmonary preparation or inhalant, or transnasal ornasal preparation in the range of 1 to 200 mg at one time or by dividingfor several times; the compound can be applied in external preparationin the range of 0.1 to 300 mg at one time or by dividing for severaltimes; and the compound can be patched in adhesive preparation in therange of 0.1 to 300 mg at one time or by dividing for several times. 2.(canceled)
 3. (canceled)
 4. The method for prevention and/or treatmentof claim 1 wherein the compound is administered in oral administrationin the range of 2 to 500 mg per day for adults at one time or bydividing for several times.
 5. The method for prevention and/ortreatment of claim 1 wherein the compound is administered intranspulmonary preparation or inhalant, or transnasal or nasalpreparation in the range of 1 to 200 mg at one time or by dividing forseveral times.
 6. A method for preventing and/or treating a chronicobstructive pulmonary disease by administering a 5-membered ringcompound of the formula (2):

or a pharmaceutically acceptable salt thereof in combination with asteroid or an anticholinergic agent as a companion drug in a dosage formselected from oral administration, injections, transpulmonarypreparation, inhalant, transnasal or nasal preparation, externalpreparation, or adhesive preparation, wherein the compound can beadministered in oral administration in the range of 2 to 500 mg per dayfor adults at one time or by dividing for several times; the compoundcan be intravenously administered in injections in the range of 1 to 200mg at one time or by dividing for several times or continuously; thecompound can be administered in transpulmonary preparation or inhalant,or transnasal or nasal preparation in the range of 1 to 200 mg at onetime or by dividing for several times; the compound can be applied inexternal preparation in the range of 0.1 to 300 mg at one time or bydividing for several times; and the compound can be administered by anadhesive patch preparation in the range of 0.1 to 300 mg at one time orby dividing for several times.
 7. The method for preventing and/ortreating a chronic obstructive pulmonary disease of claim 6 wherein thecompound is administered in oral administration in the range of 2 to 500mg per day for adults at one time or by dividing for several times. 8.The method for preventing and/or treating a chronic obstructivepulmonary disease of claim 6 wherein the compound is administered intranspulmonary preparation or inhalant, or transnasal or nasalpreparation in the range of 1 to 200 mg at one time or by dividing forseveral times.
 9. The method for preventing and/or treating a chronicobstructive pulmonary disease of claim 6 wherein the companion drug is asteroid.
 10. The method for preventing and/or treating a chronicobstructive pulmonary disease of claim 6 wherein the companion drug isan anticholinergic agent.